Abstract 3699: Involvement of p53 and KRAS in the regulation of SLC38A5 in colon cancer
Authors: Nhi Thi Nguyen, Sathish Sivaprakasam, Vadivel Ganapathy
Journal: Cancer Research (2023)

Abstract Cancer-associated upregulation has been demonstrated for selective glucose transporters and amino acid transporters. The amino acid transporter SN2 (SLC38A5) represents the latest addition to this list. Transcriptomic analysis of tumor tissues has shown SLC38A5 is upregulated in breast and colon cancer. SLC38A5 is an amino acid-dependent Na+/H+ exchanger, induced in cancer, which not only supplies amino acids to cancer cells but also maintains an alkaline intracellular pH. The substrates for SLC38A5 include glutamine, asparagine, histidine, methionine, glycine, and serine, highlighting the role of SLC38A5 in glutamine addiction and one-carbon metabolism, both pathways being essential for cancer cells. In addition, SLC38A5 activates macropinocytosis, a process involved in cellular uptake of proteins in the extracellular fluid to meet amino acid demands in cancer cells. Since the transporter is upregulated in colon cancer, we hypothesized that the multiple functions of SLC38A5 fuel the growth, proliferation, and survival in colon cancer cells and that its induction involves oncogenic mutations in p53 and KRAS that are common mediators of carcinogenesis in colon. Firstly, we used a panel of colon cancer cells and analyzed SLC38A5 expression and its functional characteristics. Next, we compared SLC38A5 expression and function between two isogenic cell lines: SW48 with and without the oncogenic mutation (G12D) in KRAS and HCT116 with and without the tumor suppressor p53. Among the colon cancer cells examined, KM12L4 showed highest expression of SLC38A5; therefore, we characterized the function of the transporter in detail in this cell line. Our studies showed that KM12L4 cells were able to take up serine, one of the substrates for SLC38A5, in a Na+-dependent manner in the presence of 5 mM tryptophan, which is not a substrate for SLC38A5 but is known to block LAT1 transporter, which also transports serine. SLC38A5 exhibited an active serine-uptake when Na+ was replaced with Li+ at a higher pH. Li+ tolerance and a higher activity at an alkaline pH are two unique features of SLC38A5. The oncogenic mutation G12D in KRAS increased SLC38A5 activity in SW48 cells. In contrast, loss of p53 decreased SLC38A5 activity in HCT116 cells. These data demonstrate that SLC38A5 is induced in colon cancer cells and its activity is increased in the presence of oncogenic KRAS mutations and suppressed when p53 is inactivated, thus providing a valuable insight into the molecular mechanisms for the upregulation of the transporter in colon cancer. We conclude that SLC38A5, an amino acids transporter, is upregulated in colon cancer and its functions are uniquely suited to promote cell proliferation and tumor growth. We also conclude that KRAS and p53 functional status play a critical role in the increased SLC38A5 expression and activity in colon cancer. These data suggest that SLC38A5 could be exploited as a drug target for cancer therapy. Citation Format: Nhi Thi Nguyen, Sathish Sivaprakasam, Vadivel Ganapathy. Involvement of p53 and KRAS in the regulation of SLC38A5 in colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3699.